Monoclonal antibodies (moAbs) are now an accepted component of therapy for the B-cell malignancies, however there is still much that we do not understand about their mechanism of action. Factors related to both the target cell and effector mechanisms appear to play important roles. There is growing evidence that combining moAb with other agents can enhance the efficacy of therapy. One such class of agents, known as immunostimulatory CpG oligodeoxynucleotides (CpG ODN), may be particularly effective due to their ability to induce coordinated production of a variety of cytokines that can enhance ADCC. CpG ODN also has effects on malignant B cells that could render them more sensitive to moAb therapy. The overall hypothesis of the current proposal is that CpG ODN, either alone or combined with other immunostimulatory agents, have effects on both malignant B cells and immune effector cells that will enhance the efficacy of anti-B cell moAb therapy. Three Specific Aims are proposed to pursue this hypothesis. Aim one will utilize murine models to determine whether agents that activate different effector cell populations, including CpG ODN of the A and B classes, IL2 and GM-CSF, are synergistic in their ability to enhance the efficacy of moAb therapy. Aim 2 will explore whether vitro therapy of Chronic Lymphocytic Leukemia (CLL) cells with CpG ODN alters the phenotype and function of the CLL cells and immune effector cells in a manner that would be expected to enhance the efficacy of moAb therapy. Aim 3 will assess whether clinical CpG ODN therapy of patients with CLL in a pilot trial is able to induce phenotypic and functional changes on the CLL cells, immune effector cells, and cytokines in a manner that would be expected to enhance the efficacy of moAb therapy. The results of these studies will allow for the rational design of the next generation of moAb-based approaches to the therapy of B-cell and other malignancies.